Jin-Jing Pei Group

Molecular mechanism of neurofibrillary degeneration

Research focus

Our main interest is to understand the molecular mechanisms underlying the neurofibrillary degeneration. Our research is trying to investigate the molecular mechanisms of abnormal hyperphosphorylated tau (synthesis, hyperphosphorylation, aggregation, microtubule binding ability, and secretion) and the interaction of Abeta with the signaling pathways that regulates tau hyperphosphorylation.

Alzheimer disease (AD) is the most common cause of dementia among the elderly population. The two protein pathologies that characterize AD are the plaques, largely composed of the amyloid-² peptide (Abeta), derived from the amyloid precursor protein (APP) and the neurofibrillary tangles (NFTs), composed of the abnormally hyperphosphorylated microtubule-associated protein tau. There are more than 80 potential phosphorylation sites of tau, for many of phospho-epitopes of tau the level is increased in AD brains. We reported that a <10-fold increase in ad brains is selectively found for p-tau epitopes t217, s202, t231, and t231 /s235 that are located at flanking region increase (zhou et al, 2006), indicating that phosphorylation of tau at these regions has certain significance in neurofibrillary degeneration.

Tau is a major protein associated with microtubule regulation that is important for neuronal structure and function. The most prevalent tauopathy is AD, in which the progression of tau pathology parallels the progression of cognitive decline. Ageing-associated hyperphosphorylation of tau at the flanking and microtubule binding regions disrupts its binding capacity to microtubule, resulting in microtubule breakdown, accumulation of NFTs and toxic species of soluble tau. p-Tau epitopes at the flanking and microtubule regions are more favourably regulated by the pro-survival signaling pathways such as protein kinase B and S6 kinase (Pei et al, 2003b; 2006), suggestion a role of them in neurofibrillary degeneration.

Ageing presents the premier risk factor for AD, the most prevalent neurodegenerative disease. How does ageing drive the pathologies? Pharmacological intervention showed that the molecular motor of aging (mammalian target of rapamycin) plays an important role in tau homeostasis (An et al, 2003; 2005).

The amyloid hypothesis suggests that AD pathogenesis is triggered by the accumulation of Abeta aggregates, due to overproduction of Abeta and/or the failure of clearance mechanisms. Abeta interacts with the signalling pathways that regulate the phosphorylation of tau, which in itself when deregulated can drive the neurodegenerative pathology termed tauopathy. A dual pathway hypothesis for late-onset AD links both Abeta and tau  into a converging neurodenerative process. These two proteins and their associated signallings such as S6K therefore represent important therapeutic targets for AD (Zhou et al, 2008). Intervention at multiple targets is needed because of the synergistic effect of different signaling pathways on tau hyperphosphorylation (Pei et al, 2003a; An et al, 2005; Zhou et al, 2009).

Our research also deals with the characterization of bionanoparticles that can pass through BBB and protect Abeta-induced toxicity and tau hyperphosphorylation (Bereczki et al, 2011).

Group members

Name Position Email
Jin-Jing Pei PhD, Associate Professor, Group leader Jin‑Jing.Pei@ki.se
Zhizhong Guan PhD, Associate Professor  Zhizhong.Guan@ki.se
Erika Bereczki PhD, Postdoc


Zhi Tang Doctoral Student  Zhi.Tang@ki.se



Karolinska Institutet. Department of Neurobiology, Care Sciences and Society, KI Alzheimer's Disease Research Center
Novum, Floor 5
SE-141 86 Stockholm

Selected publications

Bereczki E, Re F, Masserini ME, Winblad B, Pei JJ. Liposomes functionalized with acidic lipids rescue Abeta-induced toxicity in murine neuroblastoma cells.Nanomedicine. 2011 Oct;7(5):560-71

Zhou XW, Winblad B, Guan Z, Pei JJ. nteractions between glycogen synthase kinase 3beta, protein kinase B, and protein phosphatase 2A in tau phosphorylation in mouse N2a neuroblastoma cells.J Alzheimers Dis. 2009;17(4):929-37

Zhou XW, Tanila H, Pei JJ. Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Abeta overproduction. FEBS Lett. 2008 Jan 23;582(2):159-64

Zhou XW, Li X, Bjorkdahl C, Sjogren MJ, Alafuzoff I, Soininen H, Grundke-Iqbal I, Iqbal K, Winblad B, Pei JJ. Assessments of the accumulation severities of amyloid beta-protein and hyperphosphorylated tau in the medial temporal cortex of control and Alzheimer's brains. Neurobiol Dis. 2006 Jun;22(3):657-68

Pei JJ, An WL, Zhou XW, Nishimura T, Norberg J, Benedikz E, Götz J, Winblad B. P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett. 2006 Jan 9;580(1):107-14

An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B, Pei JJ. Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells. J Neurochem. 2005 Mar;92(5):1104-15

An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ. Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am J Pathol. 2003 Aug;163(2):591-607

Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. Am J Pathol. 2003 Sep;163(3):845-58

Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H, Tsujio I, Takeda M, Alafuzoff I, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K. Role of protein kinase B in Alzheimer's neurofibrillary pathology. Acta Neuropathol. 2003 Apr;105(4):381-92


Wen-Lin An, 2005: The role of p70 S6 kinase in the formation of tau pathologies in Alzheimers disease

Cecilla Björkdahl, 2007: Tau and neurofilament proteins in Alzheimers disease and related cell models.

Neurodegenerative diseases